Thyroid hormones are essential for normal growth and differentiation in mammals, and play a critical role on maintaining metabolic homeostasis. For example, thyroid hormones participate in the regulation of the metabolism of lipids, sugars, proteins and energies. Thyroid hormones also affect cardiovascular function such as heart rate, cardiac contraction, peripheral vascular resistance and the like.
A naturally occurring hormone, 3,5,3′-triiodo-L-thyronine (hereinafter referred to T3) binds to nuclear thyroid hormone receptors (hereinafter referred to TR). A complex composed of T3 and TR binds to the promoter region of T3 regulatory genes, which is referred to thyroid hormone response element, located at the upstream of target genes, and activates or suppresses the expression of the genes. Thyroid hormones exhibit the majority of actions by regulating the expression of the target genes in nucleus.
In patients with hypothyroidism, decreased body temperature, increased body weight, increased serum cholesterol, decreased cardiac functions, liver function disorders, depression, dry skins or alopecia are observed. In contrast, increased body temperature, decreased body weight, decreased serum cholesterol, tachycardia, increased stroke volume, arrhythmia or increased bone absorption are observed in patients with hyperthyroidism. As discussed above, thyroid hormones participate in the regulation of various physiological actions in vivo, and ligands having an affinity to thyroid hormone receptors have been expected to be useful as a therapeutic agent for hyperlipidemia, atherosclerosis, obesity, diabetes mellitus, arrhythmia, congestive heart failure, hypertension, depression, osteoporosis, glaucoma, skin disorders, alopecia and the like (see nonpatent literatures 1 to 17). It has been reported that the administration of a thyroid hormone ameliorated fatty liver and decreased the amount of liver fiber (see nonpatent literatures 18 to 21). It has also been demonstrated that the administration of a thyroid hormone decreased the amount of liver glutathione, and in a rat hepatocarcinogenesis model, decreased the incidence of liver cancer and suppressed metastases to lung (see nonpatent literatures 22 to 24). Accordingly, thyroid hormone receptor ligands are expected to be useful for the treatment of fatty liver, liver cirrhosis and liver cancer.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Further attempts to use thyroid hormones in the treatment of hyperlipidemia, obesity, depression or skin disorders have been made. However, it is reported that administering thyroid hormones at dosages more than those of replacement therapy is often accompanied with cardiac toxicities such as arrhythmia, angina, cardiac failure and the like (see nonpatent literatures 25 or 26).
Recent studies have reported that there are two major subtypes of thyroid hormone receptor (TR), TRα and TRβ, which are expressed in different ratios in different tissues (see nonpatent literature 27). Observations suggest that the TRα of the receptors contributes in a substantial way to cardiac toxicities (see nonpatent literatures 28 or 29). Accordingly, thyroid hormone receptor ligands which are selective to TRβ, would be a medicament with less cardiac toxicities.
Nonpatent Literatures:
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